Response:Clostridium difficile infection (CDI) is a major cause of antibiotic-associated colitis and diarrhea and a leading cause of hospital-acquired infection. It is caused by the toxin-producing, anaerobic, spore-forming bacterium Clostridium difficile.Antibiotic use is a major risk factor for CDI but epidemiological studies suggest that other factors, some modifiable, some not, can also increase the risk for CDI. Older age is an example of a non-modifiable risk factor for CDI. Some epidemiological studies suggested that taking the prostaglandin synthesis inhibiting drugs called non-steroidal anti-inflammatory drugs (NSAIDs) might also increase the risk for CDI. NSAIDs include medications such as ibuprofen, naproxen, indomethacin, and others. Because NSAID use is so common, if it is a risk factor for the acquisition of, or severity of, CDI, that would be important because that would be a modifiable risk factor.

We therefore sought to determine the impact of NSAID exposure on CDI severity in a mouse model of antibiotic-associated CDI. We also sought evidence for possible mechanisms whereby NSAIDs might increase the risk for CDI.

Professor Robert Britton PhD
Therapeutic Microbiology Laboratory
Department of Molecular Virology and Microbiology
Alkek Center for Metagenomics and Microbiome Research
Baylor College of Medicine

MedicalResearch.com Interview: How would you summarise your findings?

Response: As a brief summary of our work, certain strains of Clostridium difficile have emerged in the past 20 years that have resulted in epidemics worldwide, leading to C. difficile becoming one of the most common causes of hospital acquired infections. Two ribotypes of C. difficile, RT027 and RT078, emerged as key epidemic ribotypes associated with increased disease prevalence and increased mortality in patients. We found that both of these ribotypes have acquired the ability to consume the disaccharide trehalose by two completely independent mechanisms. We further show that trehalose enhances disease severity of C. difficile infection in a manner that requires C. difficile to metabolize trehalose in mice. We also show that trehalose is present in the distal intestine of mice and humans in concentrations that the RT027 ribotype can metabolize. Because RT027 and RT078 strains were present in clinics at least 10-20 years prior to their becoming epidemic isolates, we looked where people would acquire trehalose in the diet.

In 2000 the FDA approved trehalose for human consumption (EFSA did so in 2001) and based on the GRAS report from the FDA the amount of trehalose predicted to be consumed once released on the market would vastly increase what people get naturally from the diet. Our data support that these two ribotypes increased in prevalence due to a change in the human diet.

Antibiotics are not harmless drugs—Clostridium difficile infection, which can sometimes cause a deadly diarrhea, is a complication of antibiotic use and can occur after even one dose of an antibiotic.

The Minnesota Department of Health (MDH) is part of the larger Centers for Disease Control and Prevention (CDC) Emerging Infections Program (EIP). The healthcare-associated infection component of CDC’s EIP engages a network of state health departments and their academic medical center partners to help answer critical questions about emerging HAI threats including Clostridium difficile also known as “C. diff.”

In Minnesota, the majority of C. diff infections occur outside the hospital and are driven by antibiotic use in community or outpatient settings. In addition to routine surveillance data, we interview patients with C. diff who were not hospitalized prior to their infection to identify potential risks for developing C. diff infection, including identifying antibiotics received outside of routine healthcare settings.

Dentists prescribe approximately 10% of the antibiotics in outpatient settings, which was over 24 million prescriptions in 2013. When asked about their prescribing practices in a 2015 survey with the Minnesota Dental Association, 36% of dentists surveyed prescribed antibiotics for dental conditions that are generally not recommended to receive antibiotics according to American Dental Association (ADA) guidelines.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Many diseases and disorders are associated with “dysbiosis,” where the intestinal microbiota diversity is reduced. This contributes to disease and to the acquisition of antibiotic resistance. Fecal microbiota transplantation (FMT) is successful in conditions with pure dysbiosis (e.g. C diff infection) and a single dose of FMT is curative in most cases.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Although metronidazole remains the most commonly used drug to treat Clostridium difficile infection (CDI), there is mounting evidence that vancomycin is a better choice for some patients. Most previous studies have focused on primary clinical cure, but we were interested in downstream outcomes such as disease recurrence and mortality. We found that patients receiving metronidazole and vancomycin had similar rates of recurrence, but patients who were treated with vancomycin had lower risks of all-cause mortality. This was especially true among patients with severe Clostridium difficile.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The use of fecal microbiota transfer (FMT), which is defined as the transfer of intestinal microbiota from healthy donors to patients, has gained momentum across the globe, since it was established as a highly effective method for treatment of recurrent Clostridium difficile infection (CDI), with cure rates around 85%. However, worldwide implementation of FMT is currently limited by a lack of uniform guidelines, concerns about safety, and remaining uncertainty of long-term side effects.

In our study, we reported the long-term follow up of patients treated with FMT for recurrent CDI.
With a primary cure rate of 82%, our study supports the currently available evidence that fecal microbiota transfer is a very effective treatment for recurrent CDI. Importantly, a first post-FMT recurrence of CDI can be successfully treated with antibiotics.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Clostridium difficile can cause an infection in the colon called colitis. Symptoms include diarrhea, fever, nausea, and abdominal pain. It is an important cause of healthcare associated infections with approximately half a million C. difficile infections and 29,000 associated deaths in 2011. The Infectious Diseases Society of America and Society for Healthcare Epidemiology of America published guidelines in 2010 advising clinicians on appropriate antibiotic regimens to treat C. difficile infection. Prior studies have found that provider adherence to these guidelines, particularly in those with severe disease, is poor. However, these studies primarily involved patients treated at a single healthcare facility. We were interested in examining CDI treatment practices in a larger group of patients with C. difficile infection located across geographically diverse areas. Further we wanted to learn more about what patient characteristics might be associated with receiving guideline-adherent therapy for C. difficile infection.

We used data from the Center for Disease Control and Prevention’s Emerging Infections Program (EIP) which performs active population and laboratory-based surveillance for C. difficile infections in 10 U.S. sites and examined how 11,717 patients including 2006 with severe disease were treated. We found that provider adherence to national treatment guidelines was low with only around 40% of those with severe disease being prescribed the appropriate antibiotic treatment. Our analysis suggests that those who were tested for C. difficile in the hospital or who were admitted to the hospital around the time of diagnosis were more likely to receive recommended antibiotic therapy.

In addition, patients greater than 65 years old or with more underlying comorbidities were more likely to receive the right antibiotic treatment. We also found that after adjusting for age and underlying comorbidities, the odds of death within 30 days of diagnosis was almost 400% higher in patients who did not receive guideline-adherent therapy compared to those who did.

Dr. Daniel E. Freedberg MD MSDivision of Digestive and Liver Diseases
Columbia University Medical Center
New York, New York

MedicalResearch.com: What is the background for this study?

Response: We conducted this study because previous studies indicate that the gastrointestinal microbiome is easily shared between people who co-occupy a given space (such as a hospital room). We wondered if antibiotics might exert an effect on the local microbial environment.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Nutrient metals are known to be a critical driver of the outcome of host-pathogen interactions, and C. difficile is the most common cause of hospital-acquired infections. C. difficile infection typically occurs following antibiotic-mediated disruption of the healthy microbiome. We were interested in learning how nutrient metals can shape the microbiome and impact the outcome of Clostridium difficile infection.

We found that excess zinc alters the structure of the microbiome and increases the severity of C. difficile infection in mice.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Clostridium difficile (Cdiff) is a multidrug-resistant pathogen that takes over the colon after the good bacteria in the colon have been wiped out by antibiotic therapy. As a result, antibiotic treatment is a major risk factor for C. diff infections. Because of the ability of C. diff to inactivate the majority of the antibiotics currently available, it has become necessary to urgently develop a non-antibiotic therapy for this life-threatening infection. We know that C. diff causes disease by producing toxins, designated toxin A and B. During infection, the toxins are released into the colon resulting in diarrhea and inflammation of the colon as well as other diarrhea-associated illnesses. We also know that C. diff strains that are unable to produce toxins cannot cause disease. Therefore, the toxins are promising targets for a non-antibiotic therapy.

We reported last year that C. difficile regulates toxin production using quorum sensing — a system that allows bacteria to coordinate their biological activities as a group. Two sets of quorum-sensing genes (agr1 and agr2) were identified. These genes form part of a signaling communication system that makes a small peptide, which serves as a cue for the infecting bacterial population to turn on their toxin genes.

In this study we used genetic analysis to identify which of these two sets of genes is responsible for regulating the toxins. Our results demonstrates that agr1 is the culprit. This is because Cdiff agr1 mutant cannot produce toxins and unable to cause disease in mice, whereas the agr2 mutant can cause disease just like the wild type C.diff.

Dr. Shen: Clostridium difficile infection (CDI) is a persistent, healthcare associated infection with significant morbidity and mortality that costs the US billions of dollars annually. Prevention is imperative, particularly for patients at high risk for infection – hospitalized adults taking antibiotics. Trials have suggested probiotics may be useful in preventing CDI. We conducted a systematic review with meta-analysis in this high-risk population, hospitalized adults receiving antibiotics, to evaluate the current evidence for probiotic use for prevention of CDI.

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Longtin: Clostridium difficile is a major cause of infection in hospitalized patients. Current infection control measures to prevent the spread of C. difficile in hospitals focuses almost entirely on patients who present symptoms. Patients with symptoms of diarrhea due to C difficile are placed under isolation in hospitals (for example, healthcare workers will wear a gown and gloves when caring for them). However, many studies have shown that some patients may be asymptomatic carriers of C. difficile. These patients carry the C difficile bacteria in their digestive tract without being sick. It was known that these asymptomatic carriers could spread the bacteria to other patients, but it was unclear whether putting them into isolation would help prevent the spread of the microbe in hospitals. Our study tested the hypothesis that placing asymptomatic carriers under isolation could lead to a decrease in the number of infections with C difficile.

Medical Research: What is the background for this study? What are the main findings?

Dr. Theriot: This study is an extension of the work we did in 2014 in our Nature Communications paper (Theriot et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection, 2014). We really wanted to know how different antibiotics that varied in their mechanism of action altered the gut microbiota in different ways and also in turn how this altered the bile acids present in the small and large intestine of mice. Primary bile acids are made by the host and are further converted to secondary bile acids by members of the microbiota in the large intestine. We know from previous work that secondary bile acids can inhibit the growth of C. difficile, but no one has looked in depth at the bile acid makeup in the actual gut before in the context of C. difficile. In this study we show that specific antibiotics that significantly alter the large intestinal gut microbiota and deplete all secondary bile acids allow for C. difficile to grow without any inhibition. We also showed that C. difficile spores are always germinating in the small intestine, which means in order to prevent this pathogen from colonizing the gut, we will have to target the growth of the pathogen. Moving forward the focus will be on trying to repopulate the gut with bacteria that are capable of restoring the secondary bile acid pools in order to inhibit C. difficile.

Medical Research: What is the background for this study? What are the main findings?

Dr. Pogorzelska-Maziarz: Sharps disposal containers are ubiquitous in healthcare facilities and there is a growing trend toward hospitals using reusable sharps containers. Several research studies have raised concerns about the potential for sharps containers to become a source of pathogen transmission within the healthcare setting but this issue that has not been systematically studied. This is an important issue given that contamination of the hospital environment has been shown to be an important component of pathogen transmission.

To examine whether the use of reusable versus single use sharps containers was associated with rates of Clostridium difficile, we conducted a cross-sectional study of acute care hospitals. Survey data on the different types of sharps containers used were collected from over 600 hospitals and this data was linked to the Medicare Provider Analysis and Review (MedPAR) dataset, which contains facility characteristics and C. diff infections data. We found that hospitals using single-use containers had significantly lower rates of C. diff versus hospitals using reusable containers after controlling for hospital characteristics such as geographic region, teaching status, ownership type, hospital size and urbanicity. This is an important finding giving the ubiquitous nature of sharps containers in the health care setting, the growing trend toward hospitals using reusable sharps containers and the high burden of C. diff in the hospital setting. Continue reading →

Medical Research: What should clinicians and patients take away from your report?

Dr. Freedberg: Increased risk for C. diff should be factored into the decision to use acid suppression medications in children. Our findings imply that acid suppression medications alter the bacterial composition of the lower gastrointestinal tract.

Medical Research:What is the background for this study? What are the main findings?

Dr. DiBaise: Despite nearly 25 years of safe and effective use of proton pump inhibitors (PPI), in recent years there have been an increasing number of reports suggesting potentially harmful effects and harmful associations with their use. One such association with PPI use has been Clostridium difficile infection (CDI) which can cause severe and recurrent episodes of diarrhea. Previous reports evaluating the microbes present within the gastrointestinal tract (ie, gut microbiome) of individuals with CDI have shown a reduction in overall microbial community diversity. We studied the gut microbiome in healthy individuals both before and after using a proton pump inhibitors for one month and found a similar reduction in microbial diversity while taking the PPI that did not entirely revert back to the ‘normal’ baseline after being off the medication for a month. While this does not demonstrate a causal association between proton pump inhibitors use and CDI, it demonstrates that PPI use creates a situation in the gut microbial environment that may increase the individual’s susceptibility to CDI.

Dr. Youngster: The main finding is that oral administration seems to be as safe and effective as more traditional routes of delivery like colonoscopy or nasogastric tube. This is important as it allows Fecal microbiota transplantation (FMT) to be performed without the need of invasive procedures, making it safer, cheaper and more accessible to patients.

Response:Existing evidence reveals a wide variation in estimated excess length of hospital stay (LoS) associated with healthcare-acquired C. difficile infection (HA-CDI), ranging from 2.8 to 16.1 days. Few studies considered the time-dependent nature of healthcare-acquired C. difficile (i.e. patients that spent a longer time in hospital have an increased risk of infection), and none have considered the impact of severity of healthcare-acquired C. difficile on expected delayed discharge. Using a method that adjusted for this so-called time-dependent bias, we found that compared to non-infected patients, the excess length of stay of severe patients (defined by increased white blood cell count, serum creatinine, or temperature, or presence of colitis) was on average, twice (11.6 days; 95% CI: 3.6-19.6) that of non-severe cases (5.3 days; 95% CI: 1.1-9.5). However, severely infected patients did not have a higher daily risk of in-hospital death than non-severe patients. Overall, we estimated that healthcare-acquired C. difficile prolonged hospital stay with an average of ~7 days (95% CI: 3.5-10.9) and increased in-hospital daily death rate with 75% (Hazard Ratio (HR): 1.75; 95% CI: 1. 16 – 2.62).

MedicalResearch.com Interview with:Kelly R. Reveles, PharmD, PhD
The University of Texas College of Pharmacy

Medical Research: What are the main findings of the study?

Dr. Reveles: Our study utilized data from the Centers for Disease Control and Prevention’s National Hospital Discharge Surveys. Patients were selected for this study if they were at least 18 years of age and had an International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code for Clostridium difficile infection (CDI) (ICD-9-CM code 008.45). We found that Clostridium difficile infection incidence increased from 4.5 CDI discharges/1,000 total discharges in 2001 to 8.2 CDI discharges/1,000 total discharges in 2010. Mortality varied over the study period with peak mortality occurring in 2003 (8.7%) and the lowest rate occurring in 2009 (5.6%). Median hospital length of stay (LOS) was 8 days and remained stable over the study period. In summary, the incidence of Clostridium difficile infection in U.S. hospitals nearly doubled from 2001 to 2010, with little evidence of recent decline. Additionally, there does not appear to be a significant decline in mortality or hospital LOS among patients with Clostridium difficile infection.

Dr. Nylund: The main findings of our study were that among children who were identified as having a diagnosis of Clostridium difficile infection (CDI), CDI was about twice as likely to occur during periods when the child was taking either a proton pump inhibitor or histamine-2 receptor antagonist.

In brief, we performed a type of observational study called a self-controlled case series. Our data source was the military health system database which contains billing records for patients seen in military and civilian facilities. We identified all cases of Clostridium difficile infections in children ages 2-18 over the period of October 2001 to July 2013. We also identified periods when children were prescribed both proton pump inhibitors and histamine-2 receptor antagonists over the same time period. We compared the incidence of CDI during periods prescribed acid suppression medications to periods not prescribed these medications.Continue reading →

Clostridium difficile infections (CDI) are a growing problem related to healthcare exposure and antibiotic use. Over the last decade, these infections have been noted to present in patients from the community without traditional risk factors. We examined 132 patients over a six month period presenting to our medical center with CDI to explore the association between obesity and CDI. We hypothesized that in a group without exposure to health care facilities, the statistical significance of other risk factors such as obesity and IBD may be increased. Our results showed that patients with community onset CDI without known health exposure were 4 times more likely to be obese than their counterparts (OR, 4.06 95% CI 1.15–14.36) with known healthcare exposure. Furthermore, this former group was also statistically more obese than the general population of Massachusetts (34% vs 23%, OR 1.7, 95% CI 1.02–2.99).

We did not note a similar difference between community onset patients without healthcare exposure and patients who developed CDI in the hospital. This may be due to limitations of sample size or because obesity maybe a confounder in hospitalized patients and a marker for other conditions requiring admission.

Obesity has not previously been considered a risk factor for CDI but given the similarities in the derangement of gut microbiome in obese patients and that of patients with inflammatory bowel disease and recurrent antibiotic use, there is biological plausibility for this finding. Further prospective and translational research is required to elucidate the pathogenesis behind this observation. These findings may contribute to improved clinical surveillance of those at highest risk of disease.

Prof. Steve Allen
Professor of Paediatrics and International Health; RCPCH International Officer and David Baum Fellow
Room 314, The College of Medicine, Swansea University,
Swansea, SA2 8PP, UK.

MedicalResearch.com: What are the main findings of the study?

Answer: Overall, diarrhoea occurred in just over 10% participants and diarrhoea caused by C. difficile in about 1%. These outcomes were equally common in those taking the microbial preparation and those taking placebo.

Other outcomes (e.g. common GI symptoms, length of hospital stay, quality of life) were also much the same in the two groups. So, there was no evidence that the microbial preparation had prevented diarrhoea or had led to any other health benefit.

In agreement with previous research, serious adverse events were also similar in the two groups – so we found no evidence that the microbial preparation caused any harm.Continue reading →

Dr. Pattani:We performed a meta-analysis of 16 studies that assessed the effectiveness of probiotics administered concurrently with antibiotics compared to the use of antibiotics alone. The use of probiotics among patients in these trials reduced the risk of antibiotic-associated diarrhea by almost 40% and decreased the rate of Clostridium difficile infection by 63%. On subgroup analysis, the reduction remained statistically significant for the subgroups of good quality trials, trials in which a primarily Lactobacillus-based regimen was used, and those studies which had a follow-up period of less than 4 weeks.Continue reading →

An outbreak strain of Clostridium difficile, a bacterium that causes diarrhea and sometimes life-threatening inflammation of the colon, is common in Chicago-area acute care hospitals, an investigation published in the September issue of Infection Control and Hospital Epidemiology suggests.

In response to Illinois Department of Public Health reports of rising rates of C. difficile infection as a hospital discharge diagnosis, the Chicago and Cook County health departments surveyed 25 Chicago-area hospitals over one month in 2009. They identified 263 total cases of C. difficile illness. Of 129 C. difficile isolates cultured from these patients, 61 percent were the outbreak C. difficile strain known as BI/NAP1.

The BI strain, which is known to cause more serious illness, is usually associated with large acute outbreaks of C. difficile. However this investigation suggests that BI is endemic in the Chicago area and patients could be at risk for severe disease even in the absence of a large acute outbreak.

“Our findings highlight the need for effective interventions aimed at reducing the risk of C. difficile infection,” said Stephanie Black, MD with the Chicago Department of Public Health and the investigation’s lead author.

The investigation suggests that the transfer of patients from one facility to another has helped to spread the BI strain. Dr. Black and her team found that half of the patients with the BI strain were transferred from one healthcare facility to another. “Inter-facility transfer of recently infected patients is a plausible mechanism for the spread of the BI group and may explain in part how BI became the dominant [strain] in this region,” the authors write.

C. difficile is most common in elderly patients and those receiving treatment with antibiotics. It is considered to be one of the most important health care-related infections in the U.S.

The Society for Healthcare Epidemiology of America recommends that patients take the following steps to reduce the spread of C. difficile:

Make sure that all doctors, nurses, and other healthcare providers clean their hands with soap and water.

Only take antibiotics as prescribed by your doctor.

Be sure to clean your own hands often, especially after using the bathroom and before eating.

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